Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz.

Autor:	Jones DL; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104., Hallström GF; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104., Jiang X; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104., Locke RC; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104., Evans MK; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104., Bonnevie ED; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104., Srikumar A; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104., Leahy TP; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104., Nijsure MP; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104., Boerckel JD; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104., Mauck RL; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.; Translational Musculoskeletal Research Center, Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104., Dyment NA; Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 May 30; Vol. 120 (22), pp. e2211947120. Date of Electronic Publication: 2023 May 22.
DOI:	10.1073/pnas.2211947120
Abstrakt:	Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function are not well understood. Here, we show using a model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs, resulting in subsequent weakening of the tendon. In vitro studies using paired ATAC/RNAseq demonstrate that the loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Concordantly, the depletion of Yap/Taz elevates matrix catabolic expression. Conversely, overexpression of Yap results in a reduction of chromatin accessibility at matrix catabolic gene loci, while also reducing transcriptional levels. The overexpression of Yap not only prevents the induction of this broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force-induced alterations. Taken together, these results provide novel mechanistic details by which mechanoepigenetic signals regulate tendon cell function through a Yap/Taz axis.
Databáze:	MEDLINE
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